Using techniques developed in the uremic rat model, we have evaluated the skeletal response of patients with end-stage renal disease to 250HD3 therapy. The results demonstrated that measurements of mineral-collagen density gradient profiles of iliac crest bone biopsies prove both complimentary and more sensitive than histometric analyses in detecting early skeletal responses to therapeutic intervention. Studies in laboratory rat models with an induced systemic metabolic acidosis also revealed that circulating pH, independent of calcium or phosphate, conditions the adaptive enzymatic control of 250HD3 metabolism in the vitamin D depleted state. More recently, we have demonstrated that changes in dietary phosphate also modulate the intestinal absorption of calcium in uremic patients, and that acidosis blunts the renal response to parathyroid hormone in animals with chronic renal insufficiency.